RESUMO
The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Indóis/síntese química , Desenho de Fármacos , Humanos , Relação Estrutura-AtividadeRESUMO
The design and synthesis of a novel series of potent gamma secretase modulators is described. Exploration of various spacer groups between the triazole ring and the aromatic appendix in 2 has led to anilinotriazole 28, which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Compostos de Anilina/química , Triazóis/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina/síntese química , Compostos de Anilina/metabolismo , Animais , Encéfalo/metabolismo , Desenho de Fármacos , Humanos , Camundongos , Camundongos Transgênicos , Ligação Proteica , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/metabolismoRESUMO
The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer's drug which demonstrated high in vitro and in vivo potency against Aß42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series.
